The ubiquitous ‘cancer mutational signature’ 5 occurs specifically in cancers with deletedFHITalleles

Abstract

The FHIT gene is located at the fragile FRA3B locus where activation by carcinogen-induced and endogenous replication stress causes FHIT deletions even in normal cells over a lifetime. Our lab has shown that loss of FHIT expression causes genome instability and provides single-strand DNA substrates for APOBEC3B hypermutation, in line with evidence that FHIT locus deletions occur in many cancers. Based on these biological features, we hypothesized that FHIT loss drives development of COSMIC mutational signature 5 and here provide evidence, including data mining of >6,500 TCGA samples, that FHIT is the cancer-associated gene with copy number alterations correlating most significantly with signature 5 mutation rate. In addition, tissues of Fhit-deficient mice exhibit a mutational signature strongly resembling signature 5 (cosine similarity value = 0.89). We conclude that FHIT loss is a molecular determinant for signature 5 mutations, which occur in all cancer types early in cancer development, are clock-like, and accelerated by carcinogen exposure. Loss of FHIT caretaker function may be a predictive and preventive marker for cancer development.

Mechanisms shaping the mutational landscape of the FRA3B/FHIT‐deficient cancer genome

“…It was concluded that FHIT expression loss is likely responsible for occurrence of signature 5. In support of this conclusion, the mutation profile of Fhit‐knockout mouse cells and tissues, closely resembles signature 5 (Figure ) . Given that large fractions of leukemia, breast, lung, and gastric tumors, and many other cancer types have reduced or absent FHIT, a mutation signature caused by FHIT‐loss would be predicted to be ubiquitous in cancer, like signature 5.…”

“…Recently, it was shown that loss of FHIT mRNA expression across many cancer types is highly associated with the mutational signature 5 in those cancers, a signature previously known only to be associated with age at diagnosis. It was concluded that FHIT expression loss is likely responsible for occurrence of signature 5.…”

“…32 APO-BEC3B has been proposed to catalyze much of the mutation burden in breast cancer, 54 induce clusters of mutations at DNA breaks and translocation sites and following telomere fusion, 52,58,59 and promote mutations in gene-dense, early-replicating regions. 60 The extent to which FHIT-loss contributes to each of these mutation patterns is unknown, but the correlative data on tumor samples strongly suggest Recently, it was shown that loss of FHIT mRNA expression across many cancer types is highly associated with the mutational signature 5 in those cancers, 61 a signature previously known only to be associated with age at diagnosis. It was concluded that FHIT expression loss is likely responsible for occurrence of signature 5.…”

“…In support of this conclusion, the mutation profile of Fhit-knockout mouse cells and tissues, closely resembles signature 5 (Figure 2). 61,62 Given that large fractions of leukemia, breast, lung, and gastric tumors, and many other FIGURE 2 Similarities in the fragile histidine triad (Fhit)-knockout mutation signature and cancer signature 5. The Fhit ko mouse kidney tissue total mutation profile was adapted from figure 3 of Paisie et al 62 Human mutational signature 5 was adapted from Alexandrov et al 63 cancer types have reduced or absent FHIT, 25 a mutation signature caused by FHIT-loss would be predicted to be ubiquitous in cancer, like signature 5.…”

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“…Therefore, complementation with BRCA1 seems to have decreased the contribution of mutation signature 3, as would be expected. However, expression of BRCA1 also gives rise predominantly to mutational signature 5, which has been associated with replication stress as a result of the deletion of FHIT leading to altered regulation of the TK1 gene and decreases in nucleotide pools 47 .…”